Neuronal cell death after general anesthesia has recently been demonstrated in neonatal animal models. The possibility of anesthesia-induced neurotoxicity during an uneventful anesthetic procedure in human neonates or infants has led to serious questions about the safety of pediatric anesthesia. However, the applicability of animal data to clinical anesthesia practice remains uncertain. This paper examines the evidence for the effects of commonly used anesthetics on neuronal structure and neurocognitive function in laboratory models and evaluates its relevance to clinical care in humans. Published retrospective reviews demonstrate temporary neurological sequelae after prolonged anesthetic exposure in young children and larger studies identify long-term neurodevelopmental impairment after neonatal surgery and anesthesia. However, there are no prospective studies evaluating neurocognitive function in children after neonatal exposure to anesthetics. Given the potential magnitude of the public health importance of this issue, this review also discusses epidemiological approaches and several ongoing prospective studies that are assessing the long-term neurocognitive effects of general anesthesia on the neonate.